Drug Information

Drug (ID: DG00660) and It's Reported Resistant Information

• Name: Sonidegib
• Synonyms: Sonidegib; Erismodegib; 956697-53-3; LDE225; NVP-LDE225; Odomzo; LDE-225; NVP-LDE 225; LDE 225; UNII-0RLU3VTK5M; Sonidegib (LDE-225); LDE225 (NVP-LDE225,Erismodegib); 0RLU3VTK5M; 956697-53-3 (free base); N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)biphenyl-3-carboxamide; Odomozo; N-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide; n-(6-((2r,6s)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)biphenyl-3-carboxamide; N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridin-3-yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide; N-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide; Sonidegib [USAN:INN]; Erismodegib [USAN:INN]; Sonidegib phospate; LDE225 (NVP-LDE225; Erismodegib); Sonidegib (USAN/INN); 1218778-76-7; erismodegib (deleted INN); NVP-LDE225(Erismodegib); Sonidegib (NVP-LDE225); MLS006011198; NVP-LDE-225; SCHEMBL554455; GTPL8199; CHEMBL2105737; CHEBI:90863; EX-A409; C26H26F3N3O3; LDE225(NVP-LDE225); DTXSID501009335; BCP02275; LDE225 - NVP-LDE225; BDBM50394562; HY-16582A; MFCD16038928; NSC761385; NSC761386; s2151; ZINC68202099; AKOS015994541; BCP9001014; CCG-264935; CS-0904; DB09143; EE-0005; NSC-761385; NSC-761386; LDE225 (NVP-LDE225, Erismodegib); NCGC00250382-01; NCGC00250382-05; NCGC00250382-07; (1,1'-Biphenyl)-3-carboxamide, N-(6-((2R,6S)-2,6-dimethyl-4-morpholinyl)-3-pyridinyl)-2- methyl-4'-(trifluoromethoxy)-, rel-; [1,1'-Biphenyl]-3-carboxamide, N-[6-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-3-pyridinyl]-2-methyl-4'-(t; AC-32799; HY-10296; N-(6-((cis-2,6-Dimethylmorpholin-4-yl)-3-pyridyl)-2-methyl-3-(4-(trifluoromethoxy)phenyl)benzamide; SMR004702967; SW218115-2; X7564; D10119; BRD-K19796430-001-01-5; Q22075856; [1,1'-Biphenyl]-3-carboxamide, N-[6-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-3-pyridinyl]-2-methyl-4'-(trifluoromethoxy)-, rel-; Erismodegib; ; ; LDE 225; ; ; NVP-LDE 225; ; ; N-[6-[(2S,6R)-2,6-Dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide; N-(6-((2R,6S)-2,6-Dimethylmorpholin-4-yl)pyridin-3-yl)-2-methyl-4'- (trifluoromethoxy)biphenyl-3-carboxamide; N-(6-(cis-2,6-Dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide; N-[6-[(2R,6S)-2,6-Dimethyl-4-morphlinyl]-3-pyridinyl]-2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide; N-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-3-pyridyl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide; rel-N-[6-[(2R,6S)-2,6-Dimethyl-4-morpholinyl]-3-pyridinyl]-2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide; rel-N-{6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl}-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide
• Indication:
  In total 2 Indication(s)
  Medulloblastoma [ICD-11: 2A00]; Approved; [1]
  Skin cancer [ICD-11: 2C30-2C37]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Basal cell carcinoma [ICD-11: 2C32]; [2]
  Gorlin syndrome [ICD-11: LD24]; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [3]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [4]
• Target: Smoothened homolog (SMO); SMO_HUMAN; [1]
• Formula: C26H26F3N3O3
• IsoSMILES: C[C@@H]1CN(C[C@@H](O1)C)C2=NC=C(C=C2)NC(=O)C3=CC=CC(=C3C)C4=CC=C(C=C4)OC(F)(F)F
• InChI: 1S/C26H26F3N3O3/c1-16-14-32(15-17(2)34-16)24-12-9-20(13-30-24)31-25(33)23-6-4-5-22(18(23)3)19-7-10-21(11-8-19)35-26(27,28)29/h4-13,16-17H,14-15H2,1-3H3,(H,31,33)/t16-,17+
• InChIKey: VZZJRYRQSPEMTK-CALCHBBNSA-N
• PubChem CID: 24775005
• ChEBI ID: CHEBI:90863
• TTD Drug ID: D09BNZ
• DrugBank ID: DB09143

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Smoothened homolog (SMO) [3]

• Molecule Alteration: Missense mutation; p.I408V (c.1222A>G)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.I408V (c.1222A>G) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target

Key Molecule: Smoothened homolog (SMO) [3]

• Molecule Alteration: Missense mutation; p.A459V (c.1376C>T)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.A459V (c.1376C>T) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target

Key Molecule: Smoothened homolog (SMO) [3]

• Molecule Alteration: Missense mutation; p.C469Y (c.1406G>A)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.C469Y (c.1406G>A) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target

Key Molecule: Smoothened homolog (SMO) [3]

• Molecule Alteration: Missense mutation; p.T241M (c.722C>T)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.T241M (c.722C>T) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target

Key Molecule: Smoothened homolog (SMO) [3]

• Molecule Alteration: Missense mutation; p.W281C (c.843G>T)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.W281C (c.843G>T) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target

Key Molecule: Smoothened homolog (SMO) [3]

• Molecule Alteration: Missense mutation; p.V321M (c.961G>A)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Basal cell carcinoma tissue; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: SNP and CGH array assay
• Mechanism Description: The missense mutation p.V321M (c.961G>A) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Smoothened homolog (SMO) [4]

• Molecule Alteration: Missense mutation; p.D384N (c.1150G>A)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vitro Model: HEK293S cells; Fetal kidney; Homo sapiens (Human); CVCL_A784
• In Vivo Model: NOD/SCID mouse; Mus musculus
• Experiment for Molecule Alteration: Immunofluorescence imaging assay
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: Posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent basal cell carcinoma in vivo.

Key Molecule: Smoothened homolog (SMO) [4]

• Molecule Alteration: Missense mutation; p.S387N (c.1160G>A)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vitro Model: HEK293S cells; Fetal kidney; Homo sapiens (Human); CVCL_A784
• In Vivo Model: NOD/SCID mouse; Mus musculus
• Experiment for Molecule Alteration: Immunofluorescence imaging assay
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: Posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent basal cell carcinoma in vivo.

Key Molecule: Smoothened homolog (SMO) [4]

• Molecule Alteration: Missense mutation; p.E518K (c.1552G>A)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vitro Model: HEK293S cells; Fetal kidney; Homo sapiens (Human); CVCL_A784
• In Vivo Model: NOD/SCID mouse; Mus musculus
• Experiment for Molecule Alteration: Immunofluorescence imaging assay
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: Posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent basal cell carcinoma in vivo.

Key Molecule: Smoothened homolog (SMO) [4]

• Molecule Alteration: Missense mutation; p.N219D (c.655A>G)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vitro Model: HEK293S cells; Fetal kidney; Homo sapiens (Human); CVCL_A784
• In Vivo Model: NOD/SCID mouse; Mus musculus
• Experiment for Molecule Alteration: Immunofluorescence imaging assay
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: Posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent basal cell carcinoma in vivo.

Basal cell carcinoma [ICD-11: 2C32]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Smoothened homolog (SMO) [2]

• Molecule Alteration: Missense mutation; p.D473H (c.1417G>C)
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; N.A.
• Experiment for Drug Resistance: Efficacy analysis

Key Molecule: Smoothened homolog (SMO) [2]

• Molecule Alteration: Missense mutation; p.D473G (c.1418A>G)
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; N.A.
• Experiment for Drug Resistance: Efficacy analysis

Key Molecule: Smoothened homolog (SMO) [2]

• Molecule Alteration: Missense mutation; p.S533N (c.1598G>A)
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; N.A.
• Experiment for Drug Resistance: Efficacy analysis

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Smoothened homolog (SMO) [2]

• Molecule Alteration: Missense mutation; p.W535L (c.1604G>T)
• Sensitive Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; N.A.
• Experiment for Drug Resistance: Efficacy analysis

References

• Ref 1: Can hair re-growth be considered an early clinical marker of treatment resistance to Hedgehog inhibitors in patients with advanced basal cell carcinoma A report of two cases .J Eur Acad Dermatol Venereol. 2016 Oct;30(10):1726-1729. doi: 10.1111/jdv.13754. Epub 2016 Jul 27. 10.1111/jdv.13754
• Ref 2: An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to VismodegibClin Cancer Res. 2016 Mar 15;22(6):1325-9. doi: 10.1158/1078-0432.CCR-15-1588. Epub 2015 Nov 6.
• Ref 3: Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma. Cancer Cell. 2015 Mar 9;27(3):327-41. doi: 10.1016/j.ccell.2015.02.001.
• Ref 4: Posaconazole, a Second-Generation Triazole Antifungal Drug, Inhibits the Hedgehog Signaling Pathway and Progression of Basal Cell CarcinomaMol Cancer Ther. 2016 May;15(5):866-76. doi: 10.1158/1535-7163.MCT-15-0729-T. Epub 2016 Jan 28.